Method of treating malaria with a loweralkyl 4-hydroxy - 6,7 - disubstituted quinoline-3-carboxylates



United States Patent 0 3,549,761 METHOD OF TREATING MALARIA WITH A LOWERALKYL 4-HYDROXY 6,7 DISUBSTI- TUTED QUINOLINE-Sa-CARBOXYLATES Robert L. Clark, Woodbridge, and Michael H. Fisher, Bridgewater Township, Somerville, N.J., assignors to lJVIerck 8; Co., Inc., Rahway, N.J., a corporation of New ersey No Drawing. Continuation-impart of application Ser. No. 706,668, Feb. 19, '1968. This application Dec. 9, 1968, Ser. No. 782,453

Int. Cl. A61k 27/00 US. Cl. 424-258 6 Claims ABSTRACT OF THE DISCLOSURE Antimalarial compositions containing loweralkyl 4- hydroxy-6,7-disubstituted quinoline-3-carboxylates as an active ingredient, and methods for combatting malaria with such compositions.

This invention is a continuation-in-part of our copending application of Ser. No. 706,668 filed Feb. 19, 1968, now abandoned.

This invention relates to novel antimalarial compositions. It relates more specifically to antimalarial compositions comprising a loweralkyl 4-hydroxy-6,7-disubstituted quinoline-3-carboxylate in admixture with a pharmaceutically acceptable carrier vehicle. Further, it is concerned with the administration of such compositions as antimalarial agents.

Malaria is a serious parasitic infection normally transmitted by the bite of an infected anopheles mosquito, although it may also be produced by transfusion of blood from an infected donor. It is found most frequently in the tropics and in some tropical areas is hyperendemic. In man it is caused most frequently by the parasites Plasmodium falciparum, P. vivax and P. malariae. The acute phase of the disease is characterized by shaking chills, high fever, sweats and headache. With malaria due to P. vivax and P. malariae the patient frequently suffers relapse because of the ability of these parasites to harbor in liver cells for extended periods of time. In view of the recurrent nature of the disease, chemotherapy is used not only to treat the acute phases, but also on an extended basis as a prophylactic or suppressive therapy. Although there are now available synthetic chemicals for the treatment of malaria, the search has continued for new and/or improved antimalarials and for compounds effective against strains of Plasmodia resistant to currently available agents.

According to the present invention it has now been found that certain loweralkyl 4-hydroxy-6,7-disubstituted quinoline-B-carboxylates have a high degree of antimalarial activity, and are therefore of use and value in the treatment and prevention of malaria in humans.

3,549,761 Patented Dec. 22, 1970 ace These compounds are represented by the structural FormulaI In the above formula R represents a loweralkyl radical, and preferably one of 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl and amyl;

R and R each represent an alkyl, alkoxy, aralkoxy, or alkylamino radical, and R and R may be the same or different in any particular compound. Representative examples of the substituents R and R are:

Alkyl having 2-18 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, amyl, hexyl, octyl, decyl, and octadecyl;

Alkoxy having 2-18 carbon atoms, such as methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, methoxymethoxy, n-propoxy, amyloxy, octyloxy, nonyloxy, decyloxy, dodecyloxy, and stearyloxy;

Aralkoxy, examples of which are phenethyloxy, phenylpropoxy, benzyloxy, p-chlorobenzyloxy, p-amin0benzyloxy and the like;

Diloweralkylamino such as dliethylamino, dimethylamino, di-n-propylamino, di-n-butylamino, methyl ethylamino, di-isobutylamino and the like.

When one or both of R and R are alkylamino acid, additional salts may be obtained, and these equivalent compounds are contemplated by and embraced within this invention. Suitable non-toxic pharmaceutically acceptable salts that may be mentioned as representative are the hydrochloride, hydrobromide, sulfate, phosphate, pamoate, tartrate, maleate, succinate, salicylate, lactate, citrate and the like. Such salts are obtained by reaction of the quinoline base with a small molar excess of the organic or inorganic acid the salt of which is desired.

Specific examples of antimalarial compounds within the scope of this invention are methyl and ethyl 4-hydroxy-6-n-propyl-7-diethylamino-quinoline-3- carboxylate,

methyl 4-hydroxy-6-methyl-7-diethylamino-quinoline-3- carboxylate,

ethyl 4-hydroxy-G-n-butylJ-diethylamino-quinoline-3- carboxylate,

methyl or ethyl 4-hydroxy-6-ethyl-7-diethylaminoquinoline-3-carboxylate,

methyl 4-hydroxy-6-dodecyl-7-dipropylamino-quinoline- 3-carboxylate,

propyl 4-hydroxy-6-ethyl-7-di-n-propylamino-quinoline- 3-carboxylate,

methyl 4-hydroxy-6-dimethylamino-7-n-propyl-quinoline- 3-carboxylate,

ethyl 4-hydroxy-6-diethylamino-7-ethyl-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-dipropylamino-7-octyl-quinoline-3- carboxylate,

methyl 4-hydroxy-6-di-butoxy-7-diethylamino-quinoline- 3-carboxylate,

ethyl 4-hydroxy-6-ethoxy-7-di-n-propylamino-quinoline- 3-carboxylate,

ethyl 4-hydroxy-6-ethoxy-7-dimethylamino-quinoline-3- carboxylate,

methyl 4-hydroxy-6,7-bis-diethylamino-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-piperidyl-7-dimethylamino-quinoline- 3-carboxylate,

propyl 4-hydroxy-6-dimethylamino-7-diethylaminoquinoline-3-carboxylate,

methyl 4-hydroxy-6-n-propyl-7-isobutoxy-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-n-butyl-7-n-propoxy-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-amyl-7-benZyl0xy-quinoline-3- carboxylate,

propyl 4-hydroxy-6-n-propyl-7-ethyl-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-ethyl-7-isopropyl-quinoline-3- carboxylate,

methyl 4-hydroxy-6-methyl-7-methyl-quinoline-3- carboxylate,

methyl 4-hydroxy-6-decyl-7-ethyl-quinoline-3- carboxylate,

methyl 4-hydroxy-6-octyl-7-ethoxy-quinoline-3- carboxylate,

methyl 4-hydroxy-6-isobutoxy-7-isobutyl-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-ethoxy-7-isobutyl-quinoline-3- carboxylate,

propyl 4-hydroxy-6-n-propoxy-7-ethyl-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-decyloxy-7-ethyl-quinoline-3- carboxylate,

methyl-4-hydroxy-6-amyloxy-7-n-propyl-quinoline-3- carboxylate,

methyl 4-hydroxy-6-isobutoxy-7-isobutoxy-quinoline-3- carboxylate,

butyl 4-hydroxy-6-ethoxy-7-propoxy-quinoline-3- carboxylate,

ethyl 4-hydroxy-6-ethoxy-7-benzyloxy-quinoline-3- carboxylate, and

ethyl 4-hydroxy-6-i-butoxy-7-phenethyloxy-quinoline-3- carboxylate.

In employing these lower alkyl 4-hydroxy-6,7-disubstituted quinoline carboxylates as antimalarials, the compounds are preferably administered orally. Oral dosage forms such as capsules, tablets or powders in which the drug is intimately admixed with a non-toxic solid pharmaceutically acceptable carrier or dilutent vehicle are preferred. However, liquid formulations such as syrups, suspensions or elixirs may be used if desired. The compounds may also be administered parenterally or intravenously in which case they may be formulated as a solution or suspension in sterile physiologic saline.

Unit dosage forms such as tablets or capsules of varying strengths may be prepared, either scored or unscored, using carriers, diluents, other excipients and formulating techniques known to those skilled in this particular art.

In accordance with the invention a composition is provided in which a quinoline of Formula I above is the primary antimalarial ingredient, and in which it is supported or suspended in a solid, substantially non-toxic pharmaceutical carrier such as lactose, sucrose, starch and/or mannitol together with other excipients commonly used in the preparation of tablets such as stearic acid, magnesium stearate, gelatin and/or acacia. Known stabilizing, binding, disintegrating, flavoring, coloring and lubricating agents may be employed as desired.

These solid unit dosage forms are conveniently prepared to contain from about 5500 mg. of quinoline of Formula I since this permits adjustment of dosage regimens by administration where necessary of more than one tablet or capsule. It should also be understood that such dosage forms, as well as other compositions of the invention may also contain one or more of other antimalarial agents such as chloroquine, primaquine and chloroguanide.

In addition to solid compositions, the compounds of the invention may be administered via oral liquid compositions such as aqueous suspensions or elixirs containing suitable dispersing, suspending or flavoring agents, or administered parenterally in physiological saline or in oleaginous vehicle,

The preferred dose level for controlling malaria in humans of the novel quinoline-3-carboxylates of Formula I above is from about 102000 mg. per day. As will be understood and appreciated by those skilled in this art, the preferred or optimal dose will depend to some extent upon the species of malaria being treated, the type of treatment being used, i.e. prophylactic or therapeutic, and the particular quinoline-3-carboxylate employed. Selection of optimum dose is made without difliculty by a clinician skilled in this art. For example, treatment of acute attacks requires higher and more frequent doses whereas in suppressive or prophylactic therapy lower doses are used but over a longer period of time. When methyl 4-hydroxy-6- n-propyl-7-diethylamino-quinoline-3-carboxylate, ethyl 4- hydroxy 6 ethyl-7-diethylamino-quino1ine-3-carboxylate ethyl 4-hydroxy 6 decyl-7-diethylamino-quinoline- 3-carboxylate, or methyl 4-hydroxy-6-decyloxy-7-diethylamino-quinoline-3-carboxylate, four of the preferred compounds of this invention, are used against falciparum malaria, oral doses of about 100-1000 mg./day for 1-10 days give good results in treating an acute attack; for preventive therapy the regimen is continued for up to two weeks after the acute stage. Similar treatment is useful against acute attacks of vivax and malariae malaria, but with these strains prophylactic or suppressive therapy is continued for a much longer period of time.

The antimalarial activity of the compounds of this invention is determined using a sensitive rodent strain of malaria Plasmodium berghei since extension of survival time in the infected host is evidence of antimalarial activity in other hosts. The experiment is conducted as follows: groups of 5 mice/group are infected with a lethal dose of P. berghei (normal strain) three days prior to treatment. The compound to be tested is suspended in oil and injected subcutaneously. The mean survival time (MST) of the infected non-medicated animals is 7.0:05 days. A compound is therapeutically active when the mean survival time of the treated groups of animals is increased in comparison with the untreated groups. The extension in survival time of the treated mice is the mean survival time of the treated mice minus the mean survival time of the untreated infected controls. The compound under test is considered as curative of the infection when any mice in the treated group survive for 60 days or longer.

Table I below sets forth the results obtained with a group of representative compounds of this invention, the figures representing the extension of survival time (in days) of the treated infected animals over the untreated infected.

TABLE I COOR:

Dose, rug/kg.

l Cure.

When the above procedure is repeated using strains of P. berghei resistant to other antimalarials, the following results are obtained.

The ingredients are reduced to a substantially uniform particle size, mixed for 10 minutes, and filled into a 350 mg. gelatin capsule.

TABLE II Increase in Dose, survival Test compound P. berghei strain mgJkg. time, days (1) Methyl l-hydroxy Triazine resistant 1 40 12 (1) fi n-propyl-7-diethyl Chloroquine resistant"... 40 12 ammo.

(1) Quinllne-3-carboxylate. Diamino diphenyl sulfone resistant... 9 12 (2) Ethyl 4-hydroxy Triazine resistant 1 40 12 (2) 6-ethyl-7-diethylamino. Chloroquine resistant 14 12 (3) Quinoline-3-earboxylate. Diamino diphenyl sulione resistant... 40 12 1 4,6-diamino-l p chlorophenyl-l,Z-dihydro-2,2-dimethy1-1,3,5-triazine. The following examples are given for the purpose of illustration and not by way of limitation.

EXAMPLE 1 Tablets containing a loweralkyl 4-hydr0xy-6,7-disubstituted quinoline-3-carboxylate of Formula I above are prepared as follows:

Mg. Compound of Formula I Starch Magnesium stearate 2 Granules 115 The granules are made of 91.5% lactose, 7% starch and 1.5% sucrose. The antimalarial agent, the starch (disintegrating agent) and the magnesium stearate (lubricant) are mixed thoroughly with the granules and the resulting mixture pressed into tablets.

A 400 mg. capsule containing mg. of a compound of Formula I is prepared by intimately admixing 3000 mg. (3 gm.) of said compound with 37,000 mg. (37 gm.) of lactose. About 1 ml. of mineral oil is added (to facilitate packing of the capsule) and the resulting mixture used to fill 400 mg. capsules.

EXAMPLE 2 A dry filled capsule is prepared with the following ingredients per capsule:

Mg. Methyl 4 hydroxy-6-n-propyl-7-diethylaminoquinoline-3-carboxylate 250 Lactose, USP 96 Magnesium stearate 3.5

EXAMPLE 3 A 250 mg. compressed tablet is prepared with the following ingredients per tablet:

Methyl 4 hydroxy-6-n-propyl-7-diethylaminoquinoline-3-carboxylate 250 Lactose, USP Cornstarch, USP (as 15% paste) 6 Cornstarch 20 Magnesium stearate 3.5

The ingredients are mixed and the mixture pressed into slugs. The slugs are granulated and compressed into tablets.

EXAMPLE 4 A sterile aqueous preparation is obtained as follows:

A sterile aqueous solution is prepared with 0.9% sodium chloride, 1.0% benzyl alcohol, 04% sodium carboxymethyl cellulose and 0.2% of Polysorbate 80, 40 wt. percent of a compound of Formula I is added to the sterile vehicle and the pH adjusted to pH 7 with sodium hydroxide or hydrochloric acid solution. The mixture is brought to volume with sterile water, homogenized, and transferred aseptically to vials.

All of the compounds of Formula I above may be formulated as described above, it being further understood that modifications within the skill of the art may be made in the formulating techniques, and in the amount and transferred aseptically to vials.

EXAMPLE 5 (A) Methyl 4-hydroxy-6-n-propyl-7-diethylaminoquinoline-3-carboxylate hydrochloride Five grams of methyl 4-hydro'xy-6-n-propyl-7-diethylamino-quinoline-3-carboxylate is suspended in 15 ml. of

methanol and concentrated hydrochloric acid is added dropwise with stirring until a solution is obtained. The solution is filtered and then diluted with ether. The hydrochloride salt of the quinoline precipitates as an oil which soon crystallizes. It is recrystallized from absolute ethanol to give yellow crystals of methyl 4-hydroxy-6-n-propyl- 7-diethylamino-quinoline 3 carboxylate hydrochloride, M.P. 139-140 C.

(B) Methyl 4-hydroxy-6-n-propyl-7-diethylaminoquinoline-3-carboxylate sulfate To 500 mg. of methyl 4-hydroxy-6-n-propyl-7-diethylamino-quinoline-3-carboxylate in 5 ml. of methanol there is added dropwise concentrated sulfuric acid until the quinoline dissolves. An excess of one or two drops of sulfuric acid is then added, and the solution allowed to stand. After a few days methyl 4-hydroxy-6-n-propyl-7- diethylamino-quinoline-3-carboxylate sulfate crystallizes. It is recovered by filtration and recrystallized from absolute ethanol; double M.P. 142 C.; 230 C.

(C) Naphthalene-1,5-disulfonate salt of methyl 4-hydroxy-6-n-propyl 7 diethylamino-quinoline 3 carboxylate To a solution of 1.5 g. of 1,S-naphthalene-disulfonic acid in 7 ml. of methanol there is added a solution of 1.5 g. of methyl 4-hydroxy-6-n-propyl-7-diethylamino-quinoline-3-carboxylate in ml. of warm methanol. The mixture is stirred for a few minutes until the desired salt begins to crystallize. When crystallization is complete the pale yellow solid is collected by filtration and dried, M.P. 200 C. dec. The salt is slightly hygroscopic.

In a similar manner as that described in parts A, B, and C above, salts of other loweralkyl 4-hydroxy-6-R -7- dialkylamino-quino1ine-3-carboxylate are obtained, as for example those salts wherein the 7-substituent is dimethylamino, diethylamino, di-n-propylamino or dibutylamino and wherein the R substituent is alkyl such as methyl, ethyl, decyl, or dodecyl, alkoxy such as methoxy, isopropoxy, isobutoxy, decyloxy or dodecyloxy.

EXAMPLE 6 (A) Methyl 6-decyloxy-7-diethylamino-4-hydroxyquinoline-3-carboxylate 2-nitrophenol (27 g.) is alkylate-d with g. of bromodecane in 400 ml. of dimethyl formamide in the presence of 10.8 g. of sodium methoxide at 100 C. for 17 hours. It is purified by adding to water, extracting with hexane, washing with hexane solution, and evaporating to obtain 2-decyloxy nitrobenzene.

The above compound (11 g.) is reductively alkylated by hydrogenating in ml. of methanol and 8.8 g. of acetaldehyde in the presence of 2 g. of palladium-on-charcoal. After removing the catalyst, the product is distilled at 0.1,u. pressure at 133135 C., yielding 7 g. of Z-decyloxy-N,N-diethy1 aniline.

The above compound (7 g.) is added to 20 ml. of sulfuric acid at 08 C. The temperature is then reduced to -15 C. while a mixture of 3 ml. of concentrated nitric acid and 9 ml. of sulfuric acid are added slowly. After the addition, the temperature is allowed to rise to 0 C. and then poured into ice. After neutralizing, the resulting oil is extracted with chloroform. The solution is then washed with water, dried, and evaporated to give 2-decyloxy-5-nitro-N,N-diethyl aniline.

The above nitro compound (3 g.) is hydrogenated in 50 ml. of methanol in the presence of 1 g. of palladiumon-charcoal. After removing the catalyst, the resulting amine, 3-N,N-diethylamine-4-decyloxy aniline, is used in the next step.

The above amine (2.2 g.) is heated for one hour on the steam-bath with 2.2 g. of dimethylmethoxy methylene malonate in 20 ml. of absolute alcohol. The alcohol is removed and the residue added to ml. of dodecyl ben- Zene at 245 C. After 15 minutes, the mixture is cooled 8 and the solid product separates. After washing with acetone, there is obtained 1.1 g. of methyl 4-hydroxy-6- decyloxy-7-diethylamino-quinoline 3 carboxylate, M.P. 178-182. C.

(B) Ethyl 6-decyl-7-diethylamino-4-hydroxyquinoline-3-carboxylate To 6 g. of 4-decyl-3-diethylamino aniline is added 4 g. of diethylethoxy methylene malonate. The solution is warmed in the steam-bath for five minutes and allowed to stand at room temperature for 18 hours. Benzene (15 ml.) is added and the solvent removed in vacuo. The residue is added to 150 ml. of dodecyl benzene heated to 250 C. and agitated by a strong current of nitrogen. After 15 minutes the mixture is cooled and a gel separates which sublimes at 195 C., and 0.4 mm. Hg to give a waxy solid, which melts at 1495 C. The yield of ethyl- 6-decyl-7-diethylamino 4 hydroxy-quinoline-3-carboxylate is 1.5 g.

(C) Methyl 6-decyl-7-diethylamino-4-hydroxyquinoline-3-carboxylate The same procedure used in Example 6(B) supra is followed, except that dimethylmethoxy methylene malomate is used. The recovered gel is partially crystallized from methanol, and has a M.P. of 140-142 C.

It will also be appreciated that acid addition salts are formed in the same manner when both the substituents R and R are diloweralkylamino, in which event a disalt is obtained.

The antimalarial compounds of this invention are, for the most part, known compounds whose synthesis is described in the art. Compounds that may not be specifically described in the literature are made by processes analogous to those that are disclosed, by an appropriate choice or substitution of reagents. This will be clear to those skilled in this particular art.

The compounds of Formula I above wherein R and R are both alkyl radicals, as well as those where R is alkyl and R is alkoxy or aryloxy are not as fully disclosed in the art as the other antimalarials disclosed herein, and for that reason a detailed method for synthesizing these two classes of 6,7-disubstituted quinolines is set forth below.

(A) Methyl 4-hy-droxy-6,7-diethyl-quinoline-3- carboxylate To 37 g. of 1,2-diethy1 benzene containing a crystal of iodine is added 41.5 g. of bromine over two hours, keeping the temperature between -5 and 10 C. The mixture is allowed to stand at room temperature overnight, and then poured into an equal volume of cold water. This mixture is then extracted with three 30 ml. portions of ether. The ether extracts are combined, washed with 5% sodium hydroxide, then with water, dried and evaporated to dryness. The residue is distilled and the fraction distilling at 6162 C./0.5 mm. is the desired 4-bromo-1,2-diethyl benzene. 31.8 g. of this material is heated in a bomb tube for 20 hours at C. with 2.8 g. of copper powder, 2.4 g. of cuprous chloride and 118 ml. of ammonium hydroxide. The mixture is then removed from the bomb and the organic layer extracted with an equal volume of ether. The ether extract is then extracted with two 75 ml. portions of 2.5 N hydrogen chloride. The acidic extracts are combined and made alkaline with ammonium hydroxide. The oil which separates is extracted with ether and the ether extract washed with water, dried and evaporated to dryness to an oil consisting of 3,4-diethyl aniline.

13 g. of the aniline obtained as described above and 15.5 g. of dimethylmethoxy methylene malonate in 75 ml. of toluene is heated on a steam bath for one hour. This mixture is then evaporated to near dryness and the residue dissolved,in 75 ml. of toluene. This solution is treated with decolorizing charcoal, the charcoal removed by filtration and the solution evaporated in vacuo to dryness to give an oily residue. A small volume of petroleum ether is added to the residue and in a short time the residue crystallizes as a white solid which is used directly in the next step. A small portion is recrystallized from hexane to give substantially pure methyl a-carbomethoxy-fl- (3,4-diethylanilino)-acrylate.

The anil obtained above is added to 200 ml. of dodecyl benzene and the mixture heated at 250-255" C. for 25 minutes under a blanket of nitrogen. The reaction mixture is then cooled, 100 ml. of petroleum ether added and the liquid decanted. The solid residue is washed with 2X 20 ml. of acetone and the remaining solid collected. It is recrystallized from 150 ml. of dimethyl formamide to give substantially pure methyl 4-hydroxy-6,7-diethylquinoline-3-carboxylate, M.P. 298 C. dec. Other 6,7- dialkyl quinolines of this invention are obtained in similar fashion using the appropriate dialkyl benzene as starting material.

(B) Methyl 4-hydroxy-6-n-propyl-7-isopropoxyquinoline-3-carboxylate 34 g. of 2-allyl-5-acetamido phenol is dissolved in 300 ml. of absolute ethanol and 2 g. of platinum oxide added to this solution. The mixture is hydrogenated at room temperature with agitation and under a hydrogen pressure of 40 p.s.i.g. The hydrogenation is substantially complete in 5 minutes and at the end of this time the catalyst is removed by filtration and the filtrate containing 2 n propyl-5-acetamido phenol concentrated to a volume of about 250 ml. To this solution there is added 9.7 g. of sodium methoxide and the resulting mixture treated with 24.6 g. of isopropyl bromide in a sealed vessel at 100 C. for 12 hours. The reaction mixture is then poured into 150 ml. of ice water. The resulting mixture is extracted with three 100 ml. portions of ether. The ether extracts are combined, Washed with 5% sodium hydroxide and dried over magnesium sulfate. The ether solution is then concentrated to substantial dryness under reduced pressure and the resulting solid recrystallized from aqueous ethanol to afford crystalline 2-isopropoxy-4-acetamido-n-propyl-benzene, M.P. 86-89" C.

5.5 g. of 2-isopropoxy 4 acetamido-n-propyl benzene in 50 ml. of a 1:1 mixture of ethanol and concentrated hydrochloric acid is refluxed for minutes and the mixture is then cooled to room temperature. The resulting crystalline material is separated, dissolved in Water and the solution neutralized with sodium hydroxide. The filtrate is diluted with about ml. of water and made basic with sodium hydroxide. The two basic solutions are combined and allowed to stand. After a short time a semi-solid material separates, and this is removed and extracted into ether. The ether extracts are washed with water, dried over magnesium sulfate and then concentrated to remove the ether and afiord a residue consisting of 2-isopropoxy-4-amino n propyl benzene. This material is used directly without further purification.

3.5 g. of the foregoing amine and 3.5 g. of dimethylmethoxy methylene malonate are heated on a steam bath for 2 hours. The reaction mixture is then concentrated to about /2 volume and added directly to ml. of dodecyl benzene at 245 C. The mixture is heated for 30 minutes at 245-255 C. and then cooled to room temperature with stirring. The resulting solid is removed by filtration and washed with n-hexane and with acetone to afford substantially pure methyl 4-hydroxy-6-n-propyl- 7-isopropoxy-quinoline-3-carboxylate, M.P. 272274 C.

Other 6,7-di-substituted quinolines of this invention having a 6-alkyl and a 7-alkoxy radical are obtained according to the above procedure but using the appro: priately substituted 2-alkenyl 5 acetamido phenol and the appropriate etherifying reagent for the synthesis of the 2-alkoxy-4-acetamido alkyl benzene intermediate.

What is claimed is:

1. A method of combatting malaria which comprises administering to a Warm blooded animal an antimalarially effective amount of a compound having the formula where R is loweralkyl; and R and R each represent alkyl having 2-18 carbon atoms, alkoxy having 2-18 carbon atoms, aralkoxy selected from the group consisting of phenethyloxy, phenylpropoxy, benzyloxy, p-chlorobenzyloxy, and p-aminobenzyloxy, diloweralkylamino, or non-toxic acid addition salts of those compounds where R and R is diloweralkylamino in admixture with a pharmaceutically acceptable carrier.

2. The method of claim 1 wherein the quinoline is methyl 4-hydroxy-6-n-propyl 7 diethylamino-quinoline- 3-carboxylate.

3. The method of claim 1 wherein the quinoline is methyl 4-hydroxy-6-ethyl 7 dliethylamino-quinoline-3- carboxylate.

4. The method of claim 1 wherein the quinoline is methyl 4-hydroxy-6-decyloxy 7 diethylamino-quinoline- 3-carboxylate.

5. The method of claim 1 wherein the quinoline is methyl 4hydroxy-6-decyl 7 diethylamino-quinoline- 3-carboxylate.

6. The method of claim 1 wherein the quinoline is ethyl 4-hydroxy 6 decyl-7-diethylamino-quinoline-3- carboxylate.

References Cited UNITED STATES PATENTS 4/1968 Clark et al. 260--287 8/1968 Patchett et al. 260-287 OTHER REFERENCES JEROME D. GOLDBERG, Primary Examiner 

